Cryo-EM structures of the ABCA4 importer reveal mechanisms underlying substrate binding and Stargardt disease

Jessica Fernandes Scortecci, Laurie L. Molday, Susan B. Curtis, Fabian A. Garces, Pankaj Panwar, Filip Petegem and Robert S. Molday ()
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Jessica Fernandes Scortecci: University of British Columbia
Laurie L. Molday: University of British Columbia
Susan B. Curtis: University of British Columbia
Fabian A. Garces: University of British Columbia
Pankaj Panwar: University of British Columbia
Filip Petegem: University of British Columbia
Robert S. Molday: University of British Columbia

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: Abstract ABCA4 is an ATP-binding cassette (ABC) transporter that flips N-retinylidene-phosphatidylethanolamine (N-Ret-PE) from the lumen to the cytoplasmic leaflet of photoreceptor membranes. Loss-of-function mutations cause Stargardt disease (STGD1), a macular dystrophy associated with severe vision loss. To define the mechanisms underlying substrate binding and STGD1, we determine the cryo-EM structure of ABCA4 in its substrate-free and bound states. The two structures are similar and delineate an elongated protein with the two transmembrane domains (TMD) forming an outward facing conformation, extended and twisted exocytoplasmic domains (ECD), and closely opposed nucleotide binding domains. N-Ret-PE is wedged between the two TMDs and a loop from ECD1 within the lumen leaflet consistent with a lateral access mechanism and is stabilized through hydrophobic and ionic interactions with residues from the TMDs and ECDs. Our studies provide a framework for further elucidating the molecular mechanism associated with lipid transport and disease and developing promising disease interventions.

Date: 2021
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DOI: 10.1038/s41467-021-26161-7

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